The ability to learn and remember is essential for all aspects of life. To better understand these processes in relation to health and disease, we propose a new approach to studying how neural circuits compute, store information and control behavior. We will develop new strategies and techniques for simultaneous measurements of learned behaviors, synaptic plasticity, and neuronal activity in a live animal. We predict that microcircuits in simple organisms will be more tractable to these studies and that the lessons learned will be of immediate relevance to complex nervous systems that contain more numerous and elaborate circuits. Therefore, we plan to focus our research program on identified microcircuits in the simple nervous system of the nematode C. elegans and address the following questions: a) What changes occur during synaptic plasticity and how are these changes controlled? b) How does synaptic plasticity lead to long-lived changes in neuronal and network activity? c) How do neural networks compute information and control behavior? To begin to address the above questions, we need new tools and techniques that will facilitate our goal to measure synaptic changes that occur during learning. Towards this end, we will develop microfluidics-based conditional learning paradigms;lanthanide-based luminescence techniques for enhanced detection of synaptic proteins;and new strategies for in vivo measurements of neuronal activity using voltage-sensitive dyes. The development of these new techniques will allow real-time measurements of the changes that occur during learning and offer a better understanding of the molecular mechanisms that contribute to learning and memory. To compliment this approach, we will also develop genetic strategies for the identification and rapid cloning of new genes required for these complex processes. Public Health Relevance: The ability to learn and remember is essential for a happy and productive life. Even mild loss of one's mem